Funding opportunities

Using Human Isogenic iPSCs from Patients to Study the Mechanisms of Tauopathies

Funding Type: 
Basic Biology V
Grant Number: 
Funds requested: 
$1 423 800
Funding Recommendations: 
Recommended if funds allow
Grant approved: 
Public Abstract: 
Tauopathies are a group of devastating neurodegenerative disorders, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), linked to mutations in the neuronal protein tau. The central pathological feature among tauopathies is the accumulation of malformed versions of tau into large aggregates. These aggregates are linked to neuronal dysfunction and death; however, the underlying cellular mechanisms that lead to the symptoms of tauopathies remain unclear. Furthermore, there are no effective treatments. Studying tauopathies in the laboratory has been challenging, owing to lack of access to human brain tissue. Now, human induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to study these diseases using human neurons from patients. In fact, we have already established a human iPSC-derived neuron model of tauopathy that recapitulates key features of the diseases. The goal of this proposal is to use these iPSC lines, from patients with a tau mutation that is associated with AD, FTD, and PSP, to study the detailed molecular and cellular mechanisms of tauopathies. By studying the mechanisms of these diseases using human neurons, we aim to identify targets that may be used to develop new treatments.
Statement of Benefit to California: 
Tauopathies, a group of neurodegenerative disorders characterized by the accumulation of abnormal tau protein, are seen in the brains of patients with Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy. Together, these diseases affect over 600,000 individuals in California alone. To date, the cellular mechanisms leading to tauopathies remain unclear and there are no effective treatments for these devastating diseases. As a result, they are a significant burden to the California economy due to the big costs on healthcare and loss of productivity. We established a human neuron model of tauopathy that displays two characteristic phenotypes of the disease: tau fragmentation and neurodegeneration. The goal of this proposal is to study the detailed molecular and cellular mechanisms of tauopathies using this model. Successful completion of this research could foster the development of new technologies that could contribute to the California biotechnology industry. For example, the new cell lines generated could be valuable for biotechnology companies and researchers who are screening for drugs targeting tauopathies. Furthermore, the knowledge that will be gained through the proposed studies could lead to the development of new treatments. Thus, this research could help to improve the health of Californians and reduce the adverse impact of neurodegenerative diseases, thereby increasing productivity and enhancing quality of life.
Review Summary: 
Tauopathies are a group of neurodegenerative disorders that are all linked to mutations in the neuronal protein tau. They include Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy. A shared pathological feature among tauopathies is that tau accumulates into large aggregates that are linked to neuronal dysfunction and death. However, the underlying mechanisms that lead to these cellular symptoms are unclear. The proposed studies will model pathological aspects of these disorders in vitro using induced pluripotent stem cells (iPSCs) generated from a patient carrying a mutant form of tau. In Aim 1, the PI proposes to identify the cleavage sites within the mutant tau and determine the enzymes responsible for this process. In Aim 2 the cleavage enzyme will be blocked in mutant neurons to examine whether the cellular deficits will be rescued by preventing tau cleavage. The third aim will investigate chemical compounds targeting the function of this enzyme for the prevention of neuronal alterations. By studying the mechanisms of these diseases using human neurons, the investigative team aims to identify targets for new therapeutic treatments. Significance and Innovation - Understanding the pathogenic mechanisms by which the mutant tau protein leads to neuronal degeneration is of great relevance and significance. - The PI proposes meaningful and innovative experiments using genetically-modified iPSC-derived neurons to examine the cell biology of tau protein that is associated with multiple tauopathy diseases. - A major concerns by the reviewers is that little evidence is provided that firmly ties clinical disease progression to the fragmentation observed in vitro. - The project focuses on iPSCs from only a single patient. The reviewers felt that might be not sufficient to extrapolate more general conclusions from the results. Feasibility and Experimental Design - The experimental plan of this project is quite straightforward, well streamlined and feasible. - The preliminary data for the proposal are substantive and much of it was recently published in a high impact journal. - The overall plan is based on the assumption that increased levels of tau fragments can poison the neurons and led to the observed axonal deficits. However, the application does not provided any direct evidence for this mechanism. - A weakness in the application is that the project relies on the successful identification of an enzyme required for the tau fragmentation, and there is not sufficient detail provided to convince the reviewers that this can be accomplished. - No significant discussion of alternative approaches were presented in the grant. For example, if no candidate enzymes emerge from the work in Aim 1, subsequent studies in Aims 2 and 3 would not be possible; then it is not clear what experiments would be performed or what direction the project would take. Principal Investigator (PI) and Research Team - The principal investigator is an established PI with valuable expertise in functional neuroscience and neurodegenerative disorders with many specific interests. The PI has expertise working with human stem cells and iPSCs. - It was difficult to evaluate the qualifications of the research team as the PI is the only named investigator though it is indicated in the grant that two postdoctoral fellows will participate in the research. No specifics and CVs were provided for the other team members. Responsiveness to the RFA -The application is highly responsive to the RFA since the focus is on human iPSC-derived diseased neurons as models of the pathophysiological process.
  • Jared Roach

© 2013 California Institute for Regenerative Medicine